Organic compounds

ABSTRACT

The present invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein, which are useful for treating diseases which respond to CXCR2 receptor mediators. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

The present invention relates to organic compounds, e.g. compounds offormula (I), and uses thereof.

In one aspect the present invention provides a compound of formula I

or solvates, hydrates or pharmaceutically acceptable salts thereof,whereinR¹ is H, a 3 to 10 membered carbocyclic group optionally substituted byone or more Z groups, a 3 to 10 membered heterocyclic group optionallysubstituted by one or more Z groups, (C₁-C₄ alkyl)-3 to 10 memberedcarbocyclic group optionally substituted by one or more Z groups, (C₁-C₄alkyl)-3 to 10 membered heterocyclic group optionally substituted by oneor more Z groups, C₁-C₆ alkyl optionally substituted by one or morehalogen atoms, CN or OH groups, C₁-C₆ alkoxy optionally substituted byone or more halogen atoms or OH groups, or an ether group containing 2to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group isoptionally substituted by one or more substituents each independentlyselected from OH, halogen, a 3 to 10 membered carbocyclic groupoptionally substituted by one or more Z groups and a 3 to 10 memberedheterocyclic group optionally substituted by one or more Z groups;R² is a 3 to 10 membered carbocyclic group optionally substituted by oneor more Z groups, a 3 to 10 membered heterocyclic group optionallysubstituted by one or more Z groups, (C_(r) C₄ alkyl)-3 to 10 memberedcarbocyclic group optionally substituted by one or more Z groups, (C₁-C₄alkyl)-3 to 10 membered heterocyclic group optionally substituted by oneor more Z groups, C₁-C₆ alkyl optionally substituted by one or morehalogen atoms, CN or OH groups, C₁-C₆ alkoxy optionally substituted byone or more halogen atoms or OH groups, or an ether group containing 2to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group isoptionally substituted by one or more substituents each independentlyselected from OH, halogen, a 3 to 10 membered carbocyclic groupoptionally substituted by one or more Z groups and a 3 to 10 memberedheterocyclic group optionally substituted by one or more Z groups; orR¹ and R² together with the carbon atom to which they are attached form3 to 10 membered carbocyclic group optionally substituted by one or moreZ groups, or a 3 to 10 membered heterocyclic group optionallysubstituted by one or more Z groups;R³ is hydrogen, halogen or cyano;R⁴ is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl or (C₁-C₄alkyl)-R⁶, wherein the alkyl groups are each optionally substituted byone or more halogen atoms;R⁵ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, (C₁-C₄alkyl)-C₃-C₈ cycloalkyl or (C₁-C₄ alkyl)-C₅-C₈ cycloalkenyl, wherein thealkyl groups are each optionally substituted by one or more halogenatoms; orR⁴ and R⁵, together with the nitrogen and oxygen atoms to which they areattached, form a 5 to 10 membered heterocyclic group optionallysubstituted by one or more Z groups;R⁶ is selected from a 3 to 10 membered carbocyclic group optionallysubstituted by one or more Z groups, a 3 to 10 membered heterocyclicgroup optionally substituted by one or more Z groups, NR⁷R⁹, NR⁷(SO₂)R⁹,(SO₂)NR⁷R⁸, (SO₂)R⁹, NR⁷C(O)R⁹, C(O)NR⁷R⁹, NR⁷C(O)NR⁸R⁹, NR⁷C(O)OR⁹,C(O)OR⁷, OC(O)R⁹, OC(O)NR⁷, C(O)R⁹, SR⁷, CN and NO₂;R⁷ and R⁸ are each independently selected from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₅-C₁₀ cycloalkenyl and —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl;R⁹ is selected from H, C₁-C₆ alkyl, —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl,a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclicgroup, wherein each of the alkyl groups and ring systems is optionallysubstituted by OH, halo, C₁-C₃ alkyl and C₁-C₃ alkoxy;

X is CR¹⁴ or N;

Z is independently selected from OH; a 3 to 10 membered carbocyclicgroup; a 3 to 10 membered heterocyclic group; benzyl; C₁-C₆ alkyloptionally substituted by one or more halogen atoms, CN or OH groups;C₁-C₆ alkoxy optionally substituted by one or more halogen atoms, CN orOH groups; -Oaryl; -Obenzyl; —O(CH₂)_(a)C(O)E; NR¹⁰(SO₂)R¹²;(SO₂)NR¹⁰R¹¹; (SO₂)R¹²; NR¹⁰C(O)R¹²; C(O)NR¹⁰R¹²; NR¹⁰C(O)NR¹¹R¹²;NR¹⁰C(O)OR¹²; NR¹⁰R¹²; C(O)OR¹⁰; OC(O)R¹²; OC(O)NR¹⁰; C(O)R¹²; SR¹²; CN;NO₂; and halogen; or where there are two or more Z substitutents, two Zsubstituents together with the atoms to which they are attachedoptionally form a 5- to 7-membered carbocyclic or a 4- to 7-memberedheterocyclic substituent fused to the ring system;a is 0, 1, 2, 3 or 4, wherein the alkylene group is optionallysubstituted by OH or NH₂ when a is 1, 2, 3 or 4;

E is NR¹⁰R¹² or OR¹²;

each R¹⁹ and R¹¹ are independently selected from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₅-C₁₀ cycloalkenyl and —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl;each R¹² is selected from H, C₁-C₆ alkyl, —(C₁-C₃ alkylene)-C₃-C₁₀cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 memberedheterocyclic group, wherein each of the ring systems is optionallysubstituted by OH, halo, C₁-C₃ alkyl and C₁-C₃ alkoxy; andR¹⁴ is H or C₁-C₆ alkyl.

In an embodiment of the invention, R¹ is H or C₁-C₄ alkyl and the othervariables are as defined anywhere herein.

In a further embodiment of the invention, R² is C₁-C₆ alkyl optionallysubstituted by one or more halogen atoms, CN or OH groups, an ethergroup containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, a 4 to 6membered carbocyclic group optionally substituted by one or more Zgroups, or a 4 to 6 membered heterocyclic group optionally substitutedby one or more Z groups; and the other variables are as defined anywhereherein.

In a further embodiment of the invention, R¹ and R², together with thecarbon atom to which they are attached form a 4 to 6 memberedcarbocyclic group optionally substituted by one or more Z groups or a 4to 6 membered heterocyclic group optionally substituted by one or more Zgroups; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R³ is halogen, suitablychlorine; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R⁴ is H, C₁-C₄ alkyl, C₃-C₆cycloalkyl or (C₁-C₃ alkyl)-C₃-C₆ cycloalkyl; and the other variablesare as defined anywhere herein.

In a further embodiment of the invention, R⁵ is C₁-C₆ alkyl, suitablyC₁-C₄ alkyl, more suitably C₁-C₃ alkyl; and the other variables are asdefined anywhere herein.

In a further embodiment, R⁴ and R⁵, together with the nitrogen andoxygen atoms to which they are attached form a 5 or 6 memberedheterocyclic group. Suitably, R⁴ and R⁵, together with the nitrogen andoxygen atoms to which they are attached form a 5-membered heterocyclicgroup.

In a further embodiment, X is CR¹⁴, wherein R¹⁴ is H or C₁-C₆ alkyl.Optionally, R¹⁴ is H or methyl. Suitably X is CH.

In a further embodiment of the invention, Z is selected from C₁-C₄ alkyloptionally substituted by one or more halogen atoms or OH groups, C₁-C₄alkoxy optionally substituted by one or more halogen atoms or OH groups,halogen, OH and NR¹⁰R¹², wherein R¹⁰, R¹² and the other variables areall as defined anywhere herein.

Reference to “the other variables are all as defined anywhere herein”will be understood to mean that all of the other variables used in thedefinition of the compounds of Formula I can have any of the definitionsapplied to them hereinabove or in the claims. Thus, combinations ofsub-definitions of the variables are considered to be within the scopeof the invention. In particular, the definition of a variable in anembodiment of the invention may be combined with the definition of asecond variable from a separate embodiment of the invention.

In a further embodiment, the present invention provides a compound offormula (I) selected from:

Structure

If not otherwise defined herein:

-   -   “Alkyl” includes linear or branched C₁-C₈ alkyl, such as C₁-C₆        alkyl or C₁-C₄ alkyl, e.g. C₁-C₂ alkyl, including unsubstituted        or substituted alkyl, e.g. alkyl substituted by groups which are        conventional in organic chemistry, e.g. halogen, OH, NH₂ or        halo(C₁₋₆)alkyl,    -   “Halogen” includes fluoro, chloro, bromo, iodo, e.g. fluoro,        chloro, bromo, suitably chloro,    -   “Carbocyclic group” denotes a ring system consisting of the        relevant number of carbon atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10.        The ring system may be a single ring, a fused ring system or a        spirocyclic ring system. Furthermore, the carbocyclic group may        be saturated, partially unsaturated or aromatic. In particular,        it may include a saturated or partially unsaturated ring fused        to an aromatic ring or a second saturated or partially        unsaturated ring; or it may include two aromatic rings fused        together. Thus, “carbocyclic group” includes, for example,        cycloalkenyl, cycloalkyl, phenyl, indane, indene, naphthalene,        tetralin and azulene.    -   “aryl” denotes an aromatic carbocyclic ring system containing 6        to 14 ring carbon atoms, which may be unsubstituted or        substituted as defined.    -   “Heterocyclic group” denotes a ring system consisting of the        relevant number of member atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10,        including at least one heteroatom selected from N, O and S. The        ring system may be a single ring, a fused ring system or a        spirocyclic ring system. Furthermore, the heterocyclic group may        be saturated, partially unsaturated or aromatic (i.e.        heterocyclic includes heterocycloalkyl, heterocycloalkenyl and        heteroaryl). In particular, it may include a saturated or        partially unsaturated ring fused to an aromatic ring or a second        saturated or partially unsaturated ring; or it may include two        aromatic rings fused together. In addition, the heterocyclic        group includes a heterocyclic ring fused to a carbocyclic ring,        e.g. benzofused heterocyclic groups. Suitably, the heterocyclic        group includes 1, 2 or 3 heteroatoms selected from N, O and S.    -   “optionally substituted by one or more Z groups” denotes that        the relevant group may include one or more substituents, each        independently selected from the groups included within the        definition of Z. Thus, where there are two or more Z group        substituents, these may be the same or different.    -   “—(C₁-C₄ alkylene)-” or “—(C₁-C₃ alkylene)-” denote a        hydrocarbon linking group having the relevant number of carbon        atoms.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations, such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Compounds of formula (I) in free or pharmaceutically acceptable saltform are hereinafter referred to alternatively as compounds of theinvention.

Compounds of formula I that contain a basic centre are capable offorming acid addition salts, particularly pharmaceutically acceptableacid addition salts. Pharmaceutically acceptable acid addition salts ofthe compound of formula I include those of inorganic acids, for example,hydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids, for example aliphatic monocarboxylicacids such as formic acid, acetic acid, trifluoroacetic acid, propionicacid and butyric acid, caprylic acid, dichloroacetic acid, hippuricacid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaricacid or malic acid, gluconic acid, mandelic acid, dicarboxylic acidssuch as maleic acid or succinic acid, adipic acid, aspartic acid,fumaric acid, glutamic acid, malonic acid, sebacic acid, aromaticcarboxylic acids such as benzoic acid, p-chloro-benzoic acid, nicotinicacid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxyacids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid,1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid, ethanesulfonic acid,ethane-1,2-disulfonic acid, 2-hydroxy-ethanesulfonic acid, (+)camphor-10-sulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid or p-toluenesulfonic acid. These saltsmay be prepared from compounds of formula I by known salt-formingprocedures. Pharmaceutically acceptable solvates are generally hydrates.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, arealso capable of forming salts with bases, in particular pharmaceuticallyacceptable bases such as those well known in the art; suitable suchsalts include metal salts, particularly alkali metal or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts, orsalts with ammonia or pharmaceutically acceptable organic amines orheterocyclic bases such as ethanolamines, benzylamines or pyridine,arginine, benethamine, benzathine, diethanolamine, choline,4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methylglutamine, piperazine, triethanol-amine or tromethamine. These salts maybe prepared from compounds of formula I by known salt-formingprocedures. Compounds of formula I that contain acidic, e.g. carboxyl,groups may also exist as zwitterions with the quaternary ammoniumcentre.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallisation may be isotopicallysubstituted e.g. D₂O, d₆-acetone or d₆-DMSO.

Compounds of formula I in free form may be converted into salt form, andvice versa, in a conventional manner. The compounds in free or salt formcan be obtained in the form of hydrates or solvates containing a solventused for crystallisation. Compounds of formula I can be recovered fromreaction mixtures and purified in a conventional manner. Isomers, suchas enantiomers, may be obtained in a conventional manner, e.g. byfractional crystallisation or asymmetric synthesis from correspondinglyasymmetrically substituted, e.g. optically active, starting materials.

Some compounds of the invention contain at least one asymmetric carbonatom and thus they exist in individual optically active isomeric formsor as mixtures thereof, e.g. as racemic mixtures. In cases whereadditional asymmetric centres exist the present invention also embracesboth individual optically active isomers as well as mixtures, e.g.diastereomeric mixtures, thereof.

The invention includes all such forms, in particular the pure isomericforms. The different isomeric forms may be separated or resolved onefrom the other by conventional methods, or any given isomer may beobtained by conventional synthetic methods or; by stereospecific orasymmetric syntheses. Since the compounds of the invention are intendedfor use in pharmaceutical compositions it will readily be understoodthat they are each preferably provided in substantially pure form, forexample at least 60% pure, more suitably at least 75% pure andpreferably at least 85%, especially at least 98% pure (% are on a weightfor weight basis). Impure preparations of the compounds may be used forpreparing the more pure forms used in the pharmaceutical compositions;these less pure preparations of the compounds should contain at least1%, more suitably at least 5% and preferably from 10 to 59% of acompound of the invention.

The invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes suitable for inclusion in thecompounds of the invention include isotopes of hydrogen e.g. ²H and ³H,carbon e.g. ¹¹C, ¹³C and ¹⁴C, chlorine e.g. ³⁶Cl, fluorine e.g. ¹⁸F,iodine e.g. ¹²³I and ¹²⁵I, nitrogen e.g. ¹³N and ¹⁵N, oxygen e.g. ¹⁵O,¹⁷O and ¹⁸O, and sulfur e.g. ³⁵S.

Certain isotopically-labelled compounds of formula I, for example thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium (³H) andcarbon-14 (¹⁴C) are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium (²H) may afford certaintherapeutic advantages that result from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy.

Isotopically-labelled compounds of formula I can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying examplesusing an appropriate isotopically-labelled reagent in place of thenon-labelled reagent previously used.

Some of the compounds of Formula I may exist in different tautomericforms. Tautomerism is well known to those skilled in the art and theskilled person will readily appreciate which groups are able totautomerise to form the different tautomeric forms. The inventionincludes all tautomeric forms of the compounds of Formula I.

Any compound described herein as a compound of the present invention maybe prepared according to or analogously to a conventional method or asspecified herein. Starting materials are known or may be preparedaccording to or analogously to a conventional method or as specifiedherein.

A compound of formula I thus obtained may be converted into anothercompound of formula I, or a compound of formula I obtained in free formmay be converted into a salt of a compound of formula I and vice versa.

In another aspect the present invention provides a process for thepreparation of a compound of the present invention comprising:

reacting a compound of formula II

wherein R³, R⁴ and R⁵ are as defined above, with a compound of formulaIII

wherein X, R₁ and R₂ are as defined above, under appropriate conditions,e.g. in the presence of triethylamine, acetonitrile, methanol, for anappropriate time, e.g. 2 to 24 hours, at appropriate temperatures, e.g.room temperature, to obtain a compound of formula (I) of the invention.

Compounds of the invention, are useful as pharmaceuticals. Accordinglythe invention also provides a compound of formula I in free orpharmaceutically acceptable salt form for use as a pharmaceutical.

In another aspect the present invention provides the use of a compoundof formula (I) wherein the substituents are as defined above as apharmaceutical.

The compounds of the invention act as CXCR2 receptor antagonists,thereby inhibiting the infiltration and activation of inflammatorycells, in particular neutrophils, monocytes and CD8+ T cells andmediators involved in chronic obstructive pulmonary disease (COPD). Thecompounds of the invention therefore provide symptomatic relief andreduce disease progression.

The airways of subject with COPD exhibit an inflammatory response whichis predominantly neutrophilic. When the airways are exposed to cigarettesmoke macrophages, CD8+ T cells and epithelial cells are activated andrelease pro-inflammatory mediators, oxidants, cytokines and neutophilicchemotactic factors, IL-8, GROα, ENA-78 and leukotrienes. IL-8, GROα andENA-78 are selective chemoattractants for neutrophils. In humanneutrophils IL-8 binds two distinct receptors with similar affinity,CXCR1 and CXCR2. Closely related chemokines including GROα, β, γ, NAP-2and ENA-78 bind only to CXCR2. Inhibiting neutrophil recruitment istherefore a recognised therapeutic strategy for treating several lungdiseases. Blocking the binding of IL-8, GROα and ENA-78 to the chemokinereceptor CXCR2 can provide beneficial effects in patients with COPD bysuppressing the infiltration and activation of key inflammatory cells,thereby reducing subsequent tissue damage, mucus secretion, airflowobstruction and disease progression.

The IL-8 and GROα chemokine inhibitory properties of compounds of theinvention can be demonstrated in the following assays:

Receptor Binding Assay

[¹²⁵I] IL-8 (human recombinant) are obtained from Amersham PharmaciaBiotech, with specific activity 2000 Ci/mmol. All other chemicals are ofanalytical grade. Human recombinant CXCR2 receptor expressed in Chinesehamster ovary cells (CHO-K1) is purchased from Euroscreen. The Chinesehamster ovary membranes are prepared according to protocol supplied byEuroscreen. Membrane protein concentration is determined using a Bio-Radprotein assay. Assays are performed in a 96-well micro plate formataccording the method described in White, et al., J Biol Chem., 1998,273, 10095). Each reaction mixture contains 0.05 mg/ml CXCR2 membraneprotein in 20 mM Bis-Tris-propane, pH 8.0, containing 1.2 mM MgSO₄, 0.1mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, compound of interestpre-dissolved in dimethylsulphoxide (DMSO) so as to reach a finalconcentration of between 10 μM and 0.0005 μM (final concentration ofDMSO 2% (v/v)) is added. Binding is initiated by addition of 0.02 nM¹²⁵I-IL-8. After 2 hours at room temperature the plate is harvestedusing a Brandell™ 96-well harvester onto glass fibre filter plate (GF/c)blocked with 1% polyethyleneimine+0.5% BSA and washed 3 times with 25 mMNaCl, 10 mM TrisHCl, 1 mM MgSO₄, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. Thefilter is dried at 50° C. overnight. Backseal is applied to the plateand 50 μl of liquid scintillation fluid added. The counts are measuredon the Packard Topcount™ scintillation counter.

[³⁵S]-GTPγS Binding Assay for Human CXCR2 Receptor Using SPA Technology

[³⁵S]-GTPγS (with specific activity 1082 Ci/mmol) and wheat germagglutinin poly vinyl toluene scintillation proximity beads arepurchased from Amersham Pharmacia Biotech. The Chinese hamster ovarycell (CHO-K1) membranes expressing human CXCR2 receptors are purchasedfrom Biosignal Packard Inc. All other chemicals are of analytical grade.White non-binding surface 96 well Optiplate™ microplates are obtainedfrom Packard. Recombinant human IL-8 is synthesised, cloned andexpressed in Escherichia coli as described previously (Lindley I, etal., Proc. Natl. Acad. Sci., 1988, 85(23):9199). The assay is performedin duplicate in 96 well Optiplate™ microplate in a final volume of 250μl per well. Compounds are diluted in DMSO (0.5% final concentration)and incubated in 20 mM HEPES buffer pH 7.4 containing 10 mM MgCl₂, 100mM NaCl, 1 mM EDTA plus 100 nM IL-8, 50 μM GDP and 500 μM [³⁵S]GTPγS perwell. SPA beads (1 mg/well final concentration) were pre-mixed with themembranes (10 μg/well final concentration) in assay buffer: 20 mM HEPESbuffer pH 7.4 containing 10 mM MgCl₂, 100 mM NaCl, 1 mM EDTA. The beadmembrane mixture is added to each well, plates are sealed and incubatedat room temperature for 60 minutes. The plate is centrifuged and read onPackard TopCount™ scintillation counter, program [³⁵S dpm] for 1min/well. Data are expressed as the % response to 100 nM IL-8 minusbasal.

Chemotaxis Assay

The in vitro inhibitory properties of these compounds are determined inthe neutrophil chemotaxis assay. Assays are performed in a 96-well plateformat according to previously published method (Frevert C W, et al., JImmunolog. Methods, 1998, 213, 41). 96-well chemotaxis chambers 5 μm areobtained from Neuro Probe, all cell buffers are obtained from InvitrogenPaisley, UK, dextran-T500 and Ficoll-Paque Plus™ density gradientcentrifugation media are purchased from Pharmacia BiotechBuckinghamshire, UK. Calcein-AM dye is obtained from Molecular Probes.Neutrophils are isolated as previously described (Haslett, C., et al. AmJ Path., 1985, 119:101). Citrated whole blood is mixed with 4% (w/v)dextran-T500 and allowed to stand on ice for 30 minutes to removeerythrocytes. Granulocytes (PMN) are separated from peripheral bloodmononuclear cells by layering 15 ml of cell suspension onto 15 mlFicoll-Paque PLUS density gradient and centrifuged at 250×g for 25minutes. Following centrifugation any erythrocytes contamination of PMNpellet is removed by hypotonic shock lysis using 10 ml ice-coldendotoxin-free sterile water for 50 seconds and neutralised with 10 mlof cold 2× phosphate buffered saline. Isolated neutrophils (1×10⁷) arelabelled with the fluorochrome calcein-AM (5 μg) in a total volume of 1ml and incubated for 30 minutes at 37° C. The labelled cells are washedwith RPMI without phenol red+0.1% bovine serum albumin, prior to use thecells are counted and adjusted to a final concentration of 5×10⁶cells/ml. The labelled neutrophils are then mixed with test compounds(0.001-1000 nM) diluted in DMSO (0.1% final concentration) and incubatedfor 10 minutes at room temperature. The chemoattractants (29 μl) areplaced in the bottom chamber of a 96-well chemotaxis chamber at aconcentration between (0.1-5 nM). The polycarbonate filter (5 μm) isoverlaid on the plate, and the cells (25 μl) are loaded on the topfilter. The cells are allowed to migrate for 90 minutes at 37° C. in ahumidified incubator with 5% CO₂. At the end of the incubation period,migrated cells are quantified using a multi-well fluorescent platereader (Fluoroskan II™ Labsystems) at 485 nm excitation and 538 nmemission. Each compound is tested in quadruplet using 4 differentdonors. Positive control cells, i.e. cells that have not been treatedwith compound, are added to the bottom well. These represent the maximumchemotactic response of the cells. Negative control cells, i.e. thosethat have not been stimulated by a chemoattractant, are added to thebottom chamber. The difference between the positive control and negativecontrol represents the chemotactic activity of the cells.

The compounds of the Examples herein below have IC₅₀ values below 10 μMin the [³⁵S]-GPTγS binding assay. For instance, the compounds of theExamples shown in the below table have the IC₅₀ values stated.

Example IC₅₀ (μM) 2 0.002 3 0.026 4 0.013 5 0.033 6 0.028 7 0.004 80.005 2.13 0.006 2.17 0.008 2.19 0.009 2.23 0.021 2.27 0.234 2.32 0.0112.35 0.014 2.43 0.017 2.47 0.019 2.50 0.093 2.57 0.026 2.58 0.028 2.600.030 2.71 0.056 2.95 0.283

Having regard to their inhibition of binding of CXCR2, compounds of theinvention are useful in the treatment of conditions or diseases mediatedby CXCR2, for example inflammatory or allergic conditions or diseases,particularly chronic obstructive pulmonary airways or lung disease(COPD, COAD or COLD), including chronic bronchitis or dyspnea associatedtherewith, emphysema, bronchiolitis obliterans syndrome and severeasthma. Compounds of the present invention are further useful in thetreatment of various diseases, such as cancer, e.g. ovarian cancer,prostate cancer, melanoma including metastatic melanoma, lung cancer,e.g. non small cell lung cancer, renal cell carcinoma; tumourangiogenesis, ischaemia/reperfusion injury, delayed graft function,osteoarthritis, myeloid metaplasia with myelofibrosis, Adenomyosis,contact hypersensitivity (skin). and in wound healing. Treatment inaccordance with the invention may be symptomatic or prophylactic.

Prophylactic efficacy in the treatment of chronic bronchitis or COPDwill be evidenced by reduced frequency or severity, will providesymptomatic relief and reduce disease progression, improvement in lungfunction. It may further be evidenced by reduced requirement for other,symptomatic therapy, i.e. therapy for or intended to restrict or abortsymptomatic attack when it occurs, for example anti-inflammatory (e.g.corticosteroid) or bronchodilatory.

Other inflammatory or obstructive airways diseases and conditions towhich the invention is applicable include acute lung injury (ALI),acute/adult respiratory distress syndrome (ARDS), idiopathic pulmonaryfibrosis, fibroid lung, airway hyperresponsiveness, dyspnea, pulmonaryfibrosis, allergic airway inflammation, small airway disease, lungcarcinoma, acute chest syndrome in patients with sickle cell disease andpulmonary hypertension, as well as exacerbation of airwayshyperreactivity consequent to other drug therapy, in particular otherinhaled drug therapy. The invention is also applicable to the treatmentof bronchitis of whatever type or genesis including, e.g., acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Furtherinflammatory or obstructive airways diseases to which the invention isapplicable include pneumoconiosis (an inflammatory, commonlyoccupational, disease of the lungs, frequently accompanied by airwaysobstruction, whether chronic or acute, and occasioned by repeatedinhalation of dusts) of whatever type or genesis, including, forexample, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,siderosis, silicosis, tabacosis and byssinosis.

Compounds of the invention are also useful for treating respiratoryviral infections, which exacerbate underlying chronic conditions such asasthma, chronic bronchitis, COPD, otitis media, and sinusitis. Therespiratory viral infection treated may be associated with secondarybacterial infection, such as otitis media, sinusitis or pneumonia.

Compounds of the invention are also useful in the treatment ofinflammatory conditions of the skin, for example psoriasis, atopicdermatitis, lupus erythematosus, and other inflammatory or allergicconditions of the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, in particular diseases or conditions having aninflammatory component, for example, diseases affecting the noseincluding allergic rhinitis, e.g. atrophic, chronic, or seasonalrhinitis, inflammatory conditions of the gastrointestinal tract, forexample inflammatory bowel disease such as ulcerative colitis andCrohn's disease, diseases of the bone and joints including rheumatoidarthritis, psoriatic arthritis, and other diseases such asatherosclerosis, multiple sclerosis, and acute and chronic allograftrejection, e.g. following transplantation of heart, kidney, liver, lungor bone marrow.

Compounds of the invention are also useful in the treatment of endotoxicshock, glomerulonephritis, cerebral and cardiac ischemia, Alzheimer'sdisease, cystic fibrosis, virus infections and the exacerbationsassociated with them, acquired immune deficiency syndrome (AIDS),multiple sclerosis (MS), Helicobacter pylori associated gastritis, andcancers, particularly the growth of ovarian cancer.

Compounds of the invention are also useful for treating symptoms causedby viral infection in a human which is caused by the human rhinovirus,other enterovirus, coronavirus, herpes viruses, influenza virus,parainfluenza virus, respiratory syncytial virus or an adenovirus.Compounds of the invention are also useful for treating pancreatitis.

The effectiveness of a compound of the invention in inhibitinginflammatory conditions, for example in inflammatory airways diseases,may be demonstrated in an animal model, e.g. mouse, rat or rabbit model,of airway inflammation or other inflammatory conditions, for example asdescribed by Wada et al, J. Exp. Med (1994) 180:1135-40; Sekido et al,Nature (1993) 365:654-57; Modelska et al., Am. J. Respir. Crit. Care.Med (1999) 160:1450-56; and Laffon et al (1999) Am. J. Respir. Crit.Care Med. 160:1443-49.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory, antihistamine or anti-tussive drugsubstances, particularly in the treatment of obstructive or inflammatoryairways diseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate, or steroidsdescribed in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679(especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60,67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidalglucocorticoid receptor agonists, such as those described in DE10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO04/19935 and WO 04/26248; LTD4 antagonists such as montelukast andzafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline),Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801(Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440(Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO04/045607 and WO 04/037805; A_(2A) agonists such as those described inEP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO02/22630, WO 02/96462, and WO 03/086408; and A_(2B) antagonists such asthose described in WO 02/42298.

Suitable bronchodilatory drugs include anticholinergic or antimuscariniccompounds, in particular ipratropium bromide, oxitropium bromide,tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but alsothose described in EP 424021, U.S. Pat. No. 3,714,357, U.S. Pat. No.5,171,744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO04/05285, WO2004096800, WO2006048225 and WO2008025541; and beta-2adrenoceptor agonists such as albuterol (salbutamol), metaproterenol,terbutaline, salmeterol fenoterol, procaterol, and especially,formoterol, carmoterol and pharmaceutically acceptable salts thereof,and compounds (in free or salt or solvate form) of formula I of WO00/75114, which document is incorporated herein by reference, preferablycompounds of the Examples thereof, especially a compound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula I of WO 04/16601, and alsocompounds of EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, US2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO04/39766, WO 04/45618 WO 04/46083 and WO 04/80964.

Such antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.

Combinations of compounds of the invention and anticholinergic orantimuscarinic compounds, steroids, beta-2 agonists, PDE4 inhibitors,dopamine receptor agonists, LTD4 antagonists or LTB4 antagonists mayalso be used. Other useful combinations of compounds of the inventionwith anti-inflammatory drugs are those with other antagonists ofchemokine receptors, e.g. CCR-1, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7,CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularlyCCR-5 antagonists such as Schering-Plough antagonists SC-351125,SCH-55700 and SCH-D, Takeda antagonists such asN—[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]-tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 0066558 (particularlyclaim 8), and WO 0066559 (particularly claim 9).

In accordance with the foregoing, the invention also provides a methodfor the treatment of a condition or disease mediated by CXCR2, forexample an inflammatory or allergic condition, particularly aninflammatory or obstructive airways disease, which comprisesadministering to a subject, particularly a human subject, in needthereof an effective amount of a compound of formula I in a free orpharmaceutically acceptable salt form as hereinbefore described. Inanother aspect the invention provides the use of a compound of formulaI, in free or pharmaceutically acceptable salt form, as hereinbeforedescribed for the manufacture of a medicament for the treatment of acondition or disease mediated by CXCR2, for example an inflammatory orallergic condition or disease, particularly an inflammatory orobstructive airways disease.

The compounds of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; by inhalation, for example inthe treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

In a further aspect, the invention also provides a pharmaceuticalcomposition comprising as active ingredient a compound of formula I infree or pharmaceutically acceptable salt form, optionally together witha pharmaceutically acceptable diluent or carrier therefor. Thecomposition may contain a co-therapeutic compound such as ananti-inflammatory bronchodilatory or antihistamine drug as hereinbeforedescribed. Such compositions may be prepared using conventional diluentsor excipients and techniques known in the galenic art. Thus oral dosageforms may include tablets and capsules. Formulations for topicaladministration may take the form of creams, ointments, gels ortransdermal delivery systems, e.g. patches. Compositions for inhalationmay comprise aerosol or other atomizable formulations or dry powderformulations.

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,the compound of formula I having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture, e.g.magnesium stearate. When the composition comprises a nebulisedformulation, it preferably contains, for example, the compound offormula I either dissolved, or suspended, in a vehicle containing water,a co-solvent such as ethanol or propylene glycol and a stabiliser, whichmay be a surfactant.

The invention includes (A) a compound of the invention in inhalableform, e.g. in an aerosol or other atomisable composition or in inhalableparticulate, e.g. micronised form, (B) an inhalable medicamentcomprising a compound of the invention in inhalable form; (C) apharmaceutical product comprising such a compound of the invention ininhalable form in association with an inhalation device; and (D) aninhalation device containing a compound of the invention in inhalableform.

Dosages of compounds of the invention employed in practising the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for administration byinhalation are of the order of 0.01 to 1 mg/kg per day while for oraladministration suitable daily doses are of the order of 0.005 to 100mg/kg of total body weight. The daily parenteral dosage regimen is about0.001 to about 80 mg/kg of total body weight. The daily topical dosageregimen will preferably be from 0.1 mg to 150 mg, administered one tofour, preferably two or three times daily.

The invention is illustrated by the following Examples.

EXAMPLES

Example compounds of the present invention include compounds of formulaI are shown in Table 1 below, the method of preparation being describedhereinafter.

TABLE 1 Ex. Structure Name [M + H]⁺  1

6-Chloro-3-[3,4-dioxo-2-((R)-1- phenyl-propylamino)-cyclobut-1-enylamino]-2-hydroxy-N- methoxy-N-methyl- benzenesulfonamide 480  2

6-Chloro-2-hydroxy-N- methoxy-N-methyl-3-{2-[(R)-1-(5-methyl-furan-2-yl)- propylamino]-3,4-dioxo- cyclobut-1-enyl amino}-benzenesulfonamide 484  3

6-Chloro-3-{3,4-dioxo-2-[(S)- (tetrahydro-thiophen-3-yl)amino]-cyclobut-1- enylamino}-hydroxy-N- methoxy-N-methyl-benzenesulfonamide 448  4

6-Chloro-3-{3,4-dioxo-2-[(R)-1- (tetrahydro-furan-2-yl)-propylamino]-cyclobut-1- enylamino}-2-hydroxy-N- methoxy-N-methyl-benzenesulfonamide 474  5

6-Chloro-3-[3,4-dioxo-2-((R)-1- phenyl-ethylamino)-cyclobut-1-enylamino]-2-hydroxy-N- methoxy-N-methyl- benzenesulfonamide 466  6

6-Chloro-2-hydroxy-N- methoxy-N-methyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro- furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}- benzene sulfonamide 488  6a

3-Chloro-2-(methoxy-methyl- sulfamoyl)-6-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro- furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}- phenolate(2-hydroxy-ethyl)-trimethyl-ammonium; 488  7

6-Chloro-3-[3,4-dioxo-2-((R)-1- pyridin-2-yl-propylamino)-cyclobut-1-enylamino]-2- hydroxy-N-methoxy-N-methyl- benzenesulfonamide481  8

6-Chloro-3-[2-(1-ethyl- propylamino)-3,4-dioxo- cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N-methyl- benzenesulfonamide 432  9

3-[2-((R)-sec-Butylamino)-3,4- dioxo-cyclobut-1-enylamino]-6-chloro-2-hydroxy-N-methoxy- N-methyl-benzenesulfonamide 418 10

3-[2-((R)-sec-Butylamino)-3,4- dioxo-cyclobut-1-enylamino]-6- chloro-N-ethyl-2-hydroxy-N-methoxy- benzenesulfonamide 432 11

6-Chloro-2-hydroxy-N- methoxy-3-[2-((R)-1- methoxymethyl-2-methyl-propylamino)-3,4-dioxo- cyclobut-1-enylamino]-N-methyl-benzenesulfonamide 462 12

6-Chloro-N-ethyl-3-[2-(1-ethyl- propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2- hydroxy-N-methoxy- benzenesulfonamide 446 13

6-Chloro-3-(2-(1,1,3,3,3- hexafluoropropan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)-2-hydroxy-N- methoxy-N-methylbenzenesulfonamide 512

Referring to the Examples in Table 1 and Table 2, the compounds weresynthesized using the methods described herein, or other methods, whichare known in the art.

It should be understood that the organic compounds according to thepreferred embodiments may exhibit the phenomenon of tautomerism. As thechemical structures within this specification can only represent one ofthe possible tautomeric forms, it should be understood that thepreferred embodiments encompasses any tautomeric form of the drawnstructure.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereofas come within the scope of the above disclosure.

General Conditions:

Mass spectra were run on LCMS systems using electrospray ionization.[M+H]+ refers to mono-isotopic molecular weights. If not indicatedotherwise, the analytical conditions were as follows:

Method A Instrument Waters Acquity Column Waters BEH C18 100 × 2.1 mm,1.7 m Column 50° C. Temperature Eluents A: H2O, B: acetonitrile, bothcontaining 0.1% TFA Flow Rate 0.7 mL/min Gradient 0.25 min 5% B; 5% to95% B in 1.00 min, 0.25 min 95% B

Method B Instrument Waters Acquity Column Waters BEH C18 100 × 2.1 mm,1.7 m Column 50° C. Temperature Eluents A: H2O, B: acetonitrile, bothcontaining 0.1% TFA Flow Rate 0.7 mL/min Gradient 0.25 min 30% B; 30% to95% B in 1.00 min, 0.25 min 95% B

Method C Instrument Waters Acquity Column Waters BEH C18 100 × 2.1 mm,1.7 m Column 50° C. Temperature Eluents A: H2O, B: acetonitrile, bothcontaining 0.1% TFA Flow Rate 0.7 mL/min Gradient 0.25 min 5% B; 5% to95% B in 7.75 min, 1.00 min 95% B

NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometersusing ICON-NMR. Spectra were measured at 298K and were referenced usingthe solvent peak.

The various starting materials, intermediates, and compounds of thepreferred embodiments may be isolated and purified, where appropriate,using conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography. Unlessotherwise stated, all starting materials were obtained from commercialsuppliers and used without further purification. Salts may be preparedfrom compounds by known salt-forming procedures.

In addition various trade reagents and materials available from havebeen utilized. Such reagents and materials can be readily obtained fromthe suppliers indicated.

For the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

ABBREVIATIONS

RT room temperature

DMF N,N-dimethylformamide DIPEA N,N-diisopropylethylamine NMPN-methylpyrrolidine

THF tetrahydrofuranMeOH methanolDCM dichloromethaneEtOAc ethyl acetateEtOH ethanolLCMS liquid chromatographic mass spectroscopyTEA triethylamineTFA trifluoroacetic acidHPLC high performance liquid chromatographyCDI carbonyl diimidazoleIPA isopropyl alcohol

Preparation of Final Compounds Example 16-Chloro-3-[3,4-dioxo-2-((R)-1-phenyl-propylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

To a stirred suspension of6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A) (100 mg, 0.256 mmol) in MeCN (2 ml) and EtOH (1 ml)under N₂ at RT was added (R)-(+)-alpha-ethylbenzylamine (58.8 mg, 0.435mmol) and triethylamine (0.142 ml, 1.02 mmol) and the reaction mixturewas heated at 80° C. overnight. The reaction mixture was concentrated invacuo to give a yellow solid which was loaded onto a 1 g pre-packedsilica column, dissolving in the minimal amount of 5% MeOH in DCM.Purification was carried out eluting with 10-40% EtOAc in iso-hexane andthe appropriate fractions were concentrated under vacuum to give ayellow glassy solid. The solid was dissolved in EtOAc and washed fourtimes with 1M HCl (aq). The organic portion was dried (sodium sulfate)and concentrated in vacuo to yield a brown gummy solid. Trituration withiso-hexane afford the title compound as a solid brown solid; [M+H]⁺ 180.¹H NMR (DMSO) 0.9 (3H, t, CH3), 1.9 (2H, m, CH2), 3.0 (3H, s, CH3), 3.6(3H, s, CH3), 5.1 (1H, m, CH), 7.2-7.5 (6H, m, Ar—H), 8.0 (1H, d, Ar—H).

Examples 2 and 3

These examples namely,

6-Chloro-2-hydroxy-N-methoxy-N-methyl-3-{2-[(R)-1-(5-methyl-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide; [M+H]⁺ 484 Retention Time 5.1 mins (Method C)(Ex. 2) and6-Chloro-3-{3,4-dioxo-2-[(S)-(tetrahydro-thiophen-3-yl)amino]-cyclobut-1-enylamino}-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide;[M+H]⁺ 448 Retention Time 1.44 mins (Method A) (Ex. 3),are prepared analogously to Example 1 by replacing(R)-(+)-alpha-ethylbenzylamine with the appropriate amine.

Example 46-Chloro-3-{3,4-dioxo-2-[(R)-1-(tetrahydro-furan-2-yl)-propylamino]-cyclobut-1-enylamino}-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

To a stirred solution of6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide(Intermediate A) (500 mg, 1.279 mmol) in MeCN was added TEA (1.783 ml,12.79 mmol) and (R)-1-(tetrahydro-furan-2-yl)-propylamine (1 g, 7.74mmol) (Intermediate DA). The reaction mixture was heated to 70° C. overnight. The reaction mixture was evaporated to dryness. The residue wasdissolved in DCM and washed with 0.1M aqueous HCl. The organic layer wasdried over MgSO₄, filtered and evaporated to dryness. The diastereomerswere separated by Supercritical fluid chromatography according to thefollowing conditions:

Mobile Phase: 30% 2-Propanol/0.1% DEA/70% CO₂ Column: Chiralpak AD-H,250×10 mm id, 5 μm Detection: UV@220 nm

Flow rate: 10 ml/minSample concentration: 227 mg in 4.5 ml EtOHInjection volume: 150 μl

The separated diastereomers were each dissolved in DCM and washed withsaturated aqueous ammonium chloride. The organic layers were dried overmagnesium sulfate, filtered and evaporated to dryness to give

Diastereomer 1

SFC Retention time: 3.02 min

(M+H)⁺=474.0

1H NMR (CD3OD) 1.02 (3H, t, CH3), 1.70 (2H, m, CH2), 1.75 (1H, m, CH),1.95 (2H, m, CH2), 2.08 (1H, m, CH), 3.09 (3H, s, CH3), 3.68 (3H, s,CH3), 3.78 (1H, dd, CH), 3.90 (1H, dd, CH), 3.95 (1H, m, CH), 4.15 (1H,m, CH), 7.20 (1H, d, CH), 8.29 (1H, d, CH)

Diastereomer 2

Retention time: 4.20 min

(M+H)⁺=474.0

1H NMR (CD3OD) 1.02 (3H, t, CH3), 1.51 (1H, m, CH), 1.75 (1H, m, CH),1.95 (4H, m, 2×CH2), 3.09 (3H, s, CH3), 3.68 (3H, s, CH3), 3.78 (1H, dd,CH), 3.85 (1H, dd, CH), 3.95 (1H, dd, CH), 4.20 (1H, m, CH), 7.20 (1H,d, CH), 8.29 (1H, d, CH).

Example 56-Chloro-3-[3,4-dioxo-2-((R)-1-phenyl-ethylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N-methoxy-benzenesulfonamide

This compound was prepared analogously to Example 1 by replacing(R)-(+)-alpha-ethylbenzylamine with the appropriate amine; [M+H]⁺ 466Retention Time 5.38 mins (Method C).

Example 66-Chloro-2-hydroxy-N-methoxy-N-methyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide

To a stirred suspension of6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A) (7 g, 17.91 mmol) in MeCN (2 ml) and EtOH (1 ml) underN₂ at RT was added((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylaminepara-toluenesulfonate salt (Intermediate E) (5.67 g, 17.91 mmol) and TEA(0.999 ml, 7.16 mmol) and the reaction mixture was heated at 50° C. for16 hours. Further TEA was added (2.48 ml, 17.91 mmol) and the reactionwas heated at 50° C. for 1 hour then 60° C. for 20 hours. Further TEA(2.48 ml, 17.91 mmol) and Intermediate E (1.13 g, 3.58 mmol) was addedand the reaction was heated at 60° C. for 17.5 hours. The reactionmixture was concentrated in vacuo and partitioned between EtOAc and 1MHCl (aq). The aqueous layer was adjusted to pH 5 using 2M NaOH (aq) andextracted using EtOAc. The EtOAc layers were combined and washed withsaturated sodium bicarbonate (aq), water and brine. The organic layerwas dried (MgSO₄) and concentrated in vacuo. The resulting residue wasrecrystallised from toluene to give a light brown solid; [M+H]⁺ 488.2.¹H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.3 (1H, m) 1.6 (3H,m) 1.9 (2H, m) 3.6 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (2H, m) 4.0 (1H,m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.5 (1H, s), 10.1 (1H, s).

Example 6a3-Chloro-2-(methoxy-methyl-sulfamoyl)-6-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-phenolate(2-hydroxy-ethyl)-trimethyl-ammonium

To a stirred solution of6-Chloro-2-hydroxy-N-methoxy-N-methyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide (2.1 g, 4.3 mmol) in EtOAc (30 ml) and IPA (5 ml) at refluxwas added a solution of 45% choline hydroxide in MeOH (1.213 ml, 4.3mmol). After 20 minutes reaction mixture was cooled to room temperatureand stirring continued for 1 hour. The crystalline yellow solid wascollected by filtration; [M+H]⁺ 488.2 ¹H NMR (DMSO) 0.9 (3H, t, CH3),1.2 (3H, d, CH3), 1.3 (1H, m) 1.5 (1H, m), 1.6 (2H, m), 1.9 (2H, m) 3.0(3H, s), 3.1 (9H, s), 3.4 (2H, t), 3.6 (3H, s, CH3), 3.9 (4H, m), 4.0(1H, m), 5.3 (1H, t), 5.9 (1H, d), 7.7 (1H, d), 8.5 (1H, d), 9.6 (1H,s).

Example 76-Chloro-3-[3,4-dioxo-2-((R)-1-pyridin-2-yl-propylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

This compound was prepared analogously to Example 1 by replacing(R)-(+)-alpha-ethylbenzylamine with the appropriate amine; [M+H]⁺ 481Retention Time 1.06 mins (Method B).

Example 86-Chloro-3-[2-(1-ethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

To a stirred solution of6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added3-aminopentane (0.596 ml, 5.12 mmol). The reaction mixture was heated at50° C. overnight. The reaction mixture was concentrated in vacuo anddissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) andbrine. The EtOAc solution was dried (MgSO₄) and concentrated in vacuo.The residue was crystallized from toluene to give a solid; [M+H]⁺ 432.1.¹H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.5 (2H, m), 1.6 (2H, m), 3.0 (3H, s,CH3), 3.6 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H,d), 9.4 (1H, s), 10.1 (1H, s).

Example 93-[2-((R)-sec-Butylamino)-3,4-dioxo-cyclobut-1-enylamino]-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

To a stirred solution of6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added(R)-(−)-2-aminobutane (0.52 ml, 5.12 mmol). The reaction mixture washeated at 50° C. for 7 hours. The reaction mixture was concentrated invacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl(aq) and brine. The EtOAc solution was dried (MgSO₄) and concentrated invacuo. The residue was crystallized from toluene to give a solid; [M+H]⁺418.2. ¹H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.5 (2H, m),3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H,d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).

Example 103-[2-((R)-sec-Butylamino)-3,4-dioxo-cyclobut-1-enylamino]-6-chloro-N-ethyl-2-hydroxy-N-methoxy-benzenesulfonamide

To a stirred solution of6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide(Intermediate FA) (100 mg, 0.25 mmol) in MeCN (1 ml) and EtOH (1 ml) wasadded (R)-(−)-2-Aminobutane (30.7 mg, 0.42 mmol) followed bytriethylamine (69 μl, 0.49 mmol). The reaction mixture was heated at 70°C. for 1 hour. The reaction mixture was concentrated in vacuo anddissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) andconcentrated in vacuo. The residue was triturated with DCM to give awhite solid; [M+H]⁺ 432.2. ¹H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (6H, m),1.5-1.6 (2H, m), 3.3 (2H, m), 3.7 (3H, s, CH3) 4.1 (1H, m), 7.3 (1H, d),8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).

Example 116-Chloro-2-hydroxy-N-methoxy-3-[2-((R)-1-methoxymethyl-2-methyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-N-methyl-benzenesulfonamide

To a stirred solution of triethylamine (1.192 ml, 8.55 mmol) and(R)-2-Amino-3-methyl-butan-1-ol (Intermediate H) in EtOH (36 ml) wasadded6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A) (1.67 g, 4.27 mmol). The reaction mixture was heated at85° C. for 18 hours. The reaction mixture was concentrated in vacuo anddissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) andNaHCO3 (aq). The NaHCO3 (aq) layer was extracted with EtOAc. The EtOAclayers were combined and concentrated in vacuo. The residue was purifiedusing flash chromatography (0-10% MeOH in DCM) to furnish a brown solid[M+H]⁺ 462.0.

¹H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.9 (1H, m), 3.0 (3H, s, CH3), 3.3(3H, s, CH3), 3.5 (2H, m), 3.6 (3H, s, CH3), 4.1 (1H, m), 7.3 (1H, s),8.1 (1H, d), 8.4 (1H, d), 9.5 (1H, s), 10.2 (1H, s).

Example 126-Chloro-N-ethyl-3-[2-(1-ethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-benzenesulfonamide

To a stirred solution of6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide(Intermediate FA) (100 mg, 0.25 mmol) in THF (2 ml) was added3-aminopentane (29 mg, 0.25 mmol) The reaction mixture was heated at 50°C. overnight. Further 3-aminopentane (29 mg, 0.25 mmol) was added andthe reaction was heated at 50° C. for 7 hours. The reaction mixture wasconcentrated in vacuo and dissolved in EtOAc. The EtOAc solution waswashed with 10% citric acid (aq), brine, dried (sodium sulfate) andconcentrated in vacuo to give a solid; [M+H]⁺ 446.1. ¹H NMR (DMSO) 0.9(6H, t, 2×CH3), 1.2 (3H, t, CH3), 1.5 (2H, m), 1.6 (2H, m), 3.3 (2H, m),3.7 (3H, s, CH3) 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4(1H, s), 10.2 (1H, s).

Example 136-chloro-3-(2-(1,1,1,3,3,3-hexafluoropropan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide

6-Chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide(Intermediate A) (50 mg, 0.102 mmol) and1,1,1,3,3,3-hexafluoroisopropylamine (34.0 mg, 0.203 mmol) weredissolved THF (1 ml). To the solution was added methanesulfonic acid (7μl, 0.108 mmol) and the resultant mixture was heated at 50° C. overnight(˜18 hr). The solution was concentrated in vacuo and the residue wasre-dissolved in DMSO (900 μl). The solution was transferred to a HPLCvial and purified using mass-directed prep system using 50-98%acetonitrile in water (0.1% TFA). The solvent was removed from thepurified fraction in vacuo. The residue was re-dissolved in MeOH thesolvent was removed in vacuo to afford the title compound as an orangesolid;

MS m/z 512 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ 10.21 (1H, s), 9.70 (1H,s), 9.43 (1H, d), 8.01 (1H, d), 7.30 (1H, d), 6.05 (1H, m), 3.64 (3H,s), 3.04 (3H, s).

The compounds of the following tabulated (Table 2) are prepared by asimilar method to that of Example 1 using the appropriate startingcompounds and amines, the preparations of which are either describedherein or are commercially available.

TABLE 2 Ex. Structure IUPAC Name/NMR [M + H]+ 2.1

6-Chloro-3-[2-((R)-1-furan-2- ylmethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N- methoxy-N- methyl-benzenesulfonamide484 2.2

6-Chloro-3-[2-(1,2-dimethyl- propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N- methyl-benzenesulfonamide 432 2.3

N-Ethyl-2-hydroxy-N-methoxy-3-{2- [(R)-1-(5-methyl-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1- enylamino}-benzenesulfonamide 464 2.4

6-Chloro-3-[2-((R)-1-ethoxymethyl- propylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N- methyl-benzenesulfonamide 462 2.5

6-Chloro-2-hydroxy-N-methoxy-N- methyl-3-{2-[(R)-1-(5-methyl-thiophen-2-yl)-propylamino]-3,4- dioxo-cyclobut-1-enylamino}-enzenesulfonamide 500 2.6

6-Chloro-3-[2-((S)-1-cyclopropyl- ethylamino)-3,4-dioxo-cyclobut-1-enylamino]-2-hydroxy-N-methoxy- N-methyl-benzenesulfonamide 430 2.7

6-Chloro-3-[3,4-dioxo-2-((R)-1- pyrazin-2-yl-propylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy- N-methyl-benzenesulfonamide 482 2.8

6-Chloro-2-hydroxy-N-methoxy-3-[2- ((S)-2-methoxy-1-phenyl-ethylamino)-3,4-dioxo-cyclobut-1- enylamino]-N-methyl-benzenesulfonamide 496 2.9

6-Chloro-2-hydroxy-N-methoxy-N- methyl-3-[2-((S)-1-methyl-butylamino)-3,4-dioxo-cyclobut-1- enylamino]-benzenesulfonamide 432 2.10

3-[2-((S)-sec-Butylamino)-3,4-dioxo- cyclobut-1-enylamino]-6-chloro-2-hydroxy-N-methoxy-N-methyl- benzenesulfonamide 418 2.11

6-Chloro-3-[3,4-dioxo-2-((R)-1- thiophen-2-yl-ethylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy- N-methyl-benzenesulfonamide 472 2.12

6-Chloro-3-[3,4-dioxo-2-((R)-1- thiophen-2-yl-propylamino)-cyclobut-1-enylamino]-2-hydroxy-N- methoxy-N-methyl- benzenesulfonamide486 2.13

6-Chloro-3-{3,4-dioxo-2-[(R)-(R)- 1-(tetrahydro-furan-2-yl)-propylamino]-cyclobut-1- enylamino}-N-ethyl-2-hydroxy-N- methoxy-benzenesulfonamide ¹H NMR (DMSO) 1.05 (3H, t, CH₃), 1.3 (3H, t, CH₃, 1.7 (3H,m), 1.95 (2H, m, CH₂), 2.1 (1H, m, CH₂), 3.4 (2H, m, CH₂O), 3.75 (3H, s,CH₃O), 3.8 (1H, m), 3.9 (2H, m), 4.15 (1H, m), 7.15 (1H, d, ArH), 8.25(1H, d, ArH) 488 2.14

6-Chloro-N-ethyl-2-hydroxy-N- methoxy-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)- propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide 502 2.15

6-Chloro-3-[3,4-dioxo-2-((R)-1- pyridin-2-yl-ethylamino)-cyclobut-1-enylamino]-2-hydroxy-N-methoxy-N- methyl-benzenesulfonamide 467 2.16

3-[3,4-Dioxo-2-((R)-1-phenyl- propylamino)-cyclobut-1-enylamino]-N-ethyl-2-hydroxy-N- methoxy-benzenesulfonamide 460 2.17

6-chloro-3-(2- (dicyclopropylmethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 456 2.18

3-[4-Chloro-2-hydroxy-3- (isoxazolidine-2-sulfonyl)-phenylamino]-4-((R)- 1-pyridin-2-yl-propylamino)-cyclobut-3-ene-1,2-dione 493 2.19

6-Chloro-N-ethyl-2-hydroxy-3-(2- (isopropylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxybenzenesulfonamide 1H NMR (DMSO) 1.2 (3H, t,CH3), 1.25 (6H, d, 2 × CH3), 3.30 (2H, q, CH2), 3.70 (3H, s, CH3), 4.20(1H, m, CH), 7.25 (1H, d), 8.10 (1H, d), 8.40 (1H, d), 9.40 (1H, s),10.15 (1H, s) 418 2.20

(R)-6-chloro-2-hydroxy-3-(2-(1- hydroxypropan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N-methyl benzenesulfonamide 4202.21

(R)-6-Chloro-2-hydroxy-N-methoxy- N-methyl-3-(2-(1-(5-methylthiophen-2-yl)ethylamino)-3,4-dioxocyclobut- 1-enylamino)benzenesulfonamide 4862.22

(R)-3-(4-chloro-2-hydroxy-3- (isoxazolidin-2-ylsulfonyl)phenylamino)-4-(1-(5- methylfuran-2-yl)propylamino)cyclobut-3-ene-1,2- dione 496 2.23

6-chloro-2-hydroxy-N-methoxy-3-(2- (1-methoxypropan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methylbenzenesulfonamide ¹H NMR (DMSO) 1.2(3H, d, CH3), 3.0 (3H, s, CH3N), 3.35 (3H, s, CH3O), 3.42 (2H, m, CH2O),3.62 (3H, s, CH3O), 4.35 (1H, m, CHN), 8.05 (1H, d, ArH), 8.56 (1H, d,ArH), 434 2.24

(R)-6-chloro-2-hydroxy-3-(2-(1- hydroxybutan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide 4342.25

3-(2-((1R,2R)-2- (benzyloxy)cyclopentylamino)-3,4-dioxocyclobut-1-enylamino)-6- chloro-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide 536 2.26

6-chloro-3-(2-(1-ethoxybutan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 462 2.27

6-chloro-2-hydroxy-N-methoxy-N- methyl-3-(2-(1-(6-methylpyridin-2-yl)propylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 1H NMR(MeOD) 1.0 (3H, t, CH₃), 2.05 (2H, m, CH₂), 2.6 (3H, s, ArCH₃), 3.1 (3H,s, CH₃N), 3.7 (3H, s, CH₃O), 5.3 (1H, m, CHN), 7.2 (2H, 2 × ArH), 7.7(1H, t, ArH), 8.2 (1H, d, ArH) 495 2.28

6-chloro-3-(2-(cyclopentylamino)- 3,4-dioxocyclobut-1-enylamino)-N-ethyl-2-hydroxy-N- methoxybenzenesulfonamide 444 2.29

6-chloro-2-hydroxy-N-methoxy-N- methyl-3-(2-(1-(1-methyl-1H-pyrazol-4-yl)ethylamino)-3,4-dioxocyclobut- 1-enylamino)benzensulfonamide 4702.30

(R)-6-chloro-3-(2-(1-(2- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.31

6-chloro-3-(3,4-dioxo-2-(1-(pyrazin- 2-yl)propylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 482 2.32

3-(4-chloro-2-hydroxy-3-((S)-4- hydroxyisoxazolidin-2-ylsulfonyl)phenylamino)-4-((R)-1- ((2R,5R)-5-methyltetrahydrofuran-2-yl)propylamino)cyclobut-3-ene-1,2- dione 517 2.33

6-chloro-2-hydroxy-N-methoxy-3-(2- (1-methoxybutan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methylbenzenesulfonamide 448 2.34

(R)-6-chloro-2-hydroxy-3-(2-(1- hydroxy-3-methylbutan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide448 2.35

6-chloro-2-hydroxy-3-(2- (isopropylamino)-3,4-dioxocyclobut-1-enylamino)-N-methoxy-N- methylbenzenesulfonamide 1H NMR (DMSO) 1.25(6H, d, 2 × CH3), 3.05 (3H, s, CH3), 3.65 (3H, s, CH3), 4.20 (1H, m,CH), 7.30 (1H, d), 8.10 (1H, d), 8.40 (1H, d), 9.40 (1H, s), 10.15 (1H,s) 404 2.36

6-chloro-2-hydroxy-N-(2- methoxyethoxy)-N-methyl-3-(2-((R)-1-((2R,5R)-5-methyltetrahydrofuran- 2-yl)propylamino)-3,4-dioxocyclobut-1-enylamino)benzenesulfonamide 532 2.37

3-(4-chloro-2-hydroxy-3-((R)-4- hydroxyisoxazolidin-2-ylsulfonyl)phenylamino)-4-((R)-1-(5- methylfuran-2-yl)propylamino)cyclobut-3-ene-1,2- dione 512 2.38

(S)-3-(2-(sec-butylamino)-3,4- dioxocyclobut-1-enylamino)-6-chloro-N-ethyl-2-hydroxy-N- methoxybenzenesulfonamide 432 2.39

(R)-6-chloro-2-hydroxy-N-methoxy- 3-(2-(1-(3-methoxyphenyl)ethylamino)-3,4- dioxocyclobut-1-enylamino)-N-methylbenzenesulfonamide 496 2.40

6-chloro-3-(2-(1-ethoxy-3- methylbutan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 476 2.41

6-chloro-3-(2-(1-(4- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.42

6-chloro-3-(3,4-dioxo-2-(pentan-2- ylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 432 2.43

(R)-6-chloro-N-ethyl-2-hydroxy-N- methoxy-3-(2-(1-(5-methylfuran-2-yl)propylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 4982.44

(R)-6-chloro-3-(2-(1-ethoxypropan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 448/450 2.45

6-chloro-3-(2-(3,3-dimethylbutan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 446 2.46

(R)-6-chloro-2-hydroxy-N-methoxy- N-methyl-3-(2-(3-methylbutan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 432 2.47

(S)-6-chloro-3-(2-(1-ethoxypropan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 448/450 2.48

(S)-6-chloro-3-(2-(1-(2- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.49

(R)-6-chloro-3-(3,4-dioxo-2-(1- (pyridin-2-yl)propylamino)cyclobut-1-enylamino)-N-ethyl-2-hydroxy-N- methoxybenzenesulfonamide 495 2.50

6-chloro-3-(3,4-dioxo-2-(1-(pyridin-3- yl)propylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide ¹H NMR (MeOD)1.03 (3H, t, CH₃), 2.05 (2H, m, CH₂), 3.08 (3H, s, CH₃N), 3.68 (3H, s,CH₃O), 5.3 (1H, t, CHN), 7.18 (1H, d, ArH), 7.5 (1H, m, ArH), 7.9 (1H,d, ArH), 8.28 (1H, d, ArH), 8.5 (1H, d, ArH), 8.62 (1H, s, ArH). 4812.51

(S)-6-chloro-2-hydroxy-N-methoxy- N-methyl-3-(2-(1-(1-methyl-1H-pyrazol-4-yl)ethylamino)-3,4- dioxocyclobut-1-enylamino)benzenesulfonamide 470 2.52

(R)-3-(2-(1-(benzyloxy)butan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-6-chloro-2-hydroxy-N- methoxy-N- methylbenzenesulfonamide 5242.53

(R)-6-chloro-3-(2-(1-(4- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.54

(S)-6-chloro-3-(2-(3,3- dimethylbutan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 446 2.55

6-chloro-3-(2-(1-(2- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.56

(S)-6-chloro-2-hydroxy-N-methoxy- N-methyl-3-(2-(3-methylbutan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 432 2.57

6-chloro-3-(2-(heptan-4-ylamino)- 3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 460 2.58

(R)-6-chloro-3-(3,4-dioxo-2-(1- phenylethylamino)cyclobut-1-enylamino)-N-ethyl-2-hydroxy-N- methoxybenzenesulfonamide ¹H NMR (DMSO)1.20 (3H, t, CH3), 1.60 (3H, d, CH3), 3.30 (2H, q, CH2), 3.70 (3H, s,CH3), 5.35 (1H, m, CH), 7.25 (1H, d), 7.30 (1H, m), 7.40 (4H, m), 8.10(1H, d), 8.80 (1H, d), 9.40 (1H, s), 10.15 (1H, s) 480 2.59

(R)-6-chloro-3-(2-(1-(4- fluorophenyl)ethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 484 2.60

6-chloro-3-(2-(cyclopentylamino)- 3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 430 2.61

(R)-6-chloro-3-(3,4-dioxo-2-(pentan- 2-ylamino)cyclobut-1-entylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 432 2.62

(S)-6-chloro-N-ethyl-2-hydroxy-N- methoxy-3-(2-(1-methoxybutan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 462 2.63

3-(4-chloro-2-hydroxy-3-((R)-4- hydroxyisoxazolidin-2-ylsulfonyl)phenylamino)-4-((R)-1- ((2R,5R)-5-methyltetrahydrofuran-2-yl)propylamino)cyclobut-3-ene-1,2- dione 517 2.64

(S)-6-chloro-2-hydroxy-3-(2-(1- hydroxypropan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenezenesulfonamide 4202.65

(S)-6-chloro-N-ethyl-2-hydroxy-N- methoxy-3-(2-(2-methoxy-1-phenylethylamino)-3,4- dioxocyclobut-1- enylamino)benzenesulfonamide 5102.66

(R)-6-chloro-2-hydroxy-3-(2-(3- hydroxy-1-phenylpropylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide 4962.67

6-chloro-3-(2-(1-(4- ethylphenyl)ethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 494 2.68

N-ethyl-2-hydroxy-N-methoxy-3-(2- ((R)-1-((2R,5R)-5-methyltetrahydrofuran-2- yl)propylamino)-3,4-dioxocyclobut-1-enylamino)benzenesulfonamide 468 2.69

(S)-6-chloro-3-(2-(1-(4- fluorophenyl)propan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 498 2.70

(R)-6-chloro-3-(2-(1- cyclopropylethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 430 2.71

3-(3,4-dioxo-2-((R)-1-((S)- tetrahydrofuran-2-yl)propylamino)cyclobut-1- enylamino)-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide ¹H NMR (DMSO) 0.95 (3H, t, CH₃), 1.2 (3H, t,CH₃), 1.6 (2H, m), 1.7 (1H, m), 1.85 (2H, m), 1.95 (1H,. m), 3.1 (2H, m,CH₂N), 3.65 (1H, m, CHN), 3.8 (3H, s, CH₃ON), 3.9 (1H, m, CHO), 4.1 (2H,m, CH₂O), 7.4 (1H, d, ArH), 8.0 (1H, d, ArH), 8.3 (1H, d, ArH) 464 2.72

(R)-6-chloro-3-(3,4-dioxo-2-(1- phenylpropylamino)cyclobut-1-enylamino)-N-ethyl-2-hydroxy-N- methoxybenzenesulfonamide 494 2.73

3-(4-chloro-2-hydroxy-3- (isoxazolidin-2-ylsulfonyl)phenylamino)-4-((R)-1- ((2R,5R)-5-methyltetrahydrofuran-2-yl)propylamino)cyclobut-3-ene-1,2- dione 493 2.74

6-chloro-2-hydroxy-N-methoxy-N- methyl-3-(2-(2-methylcyclohexylamino)-3,4- dioxocyclobut-1-enylamino)benzenesulfonamide 458 2.75

(S)-6-chloro-3-(2-(1-ethoxybutan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 462 2.76

(S)-6-chloro-3-(2-(1-(furan-2- yl)butan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 484 2.77

(R)-6-chloro-3-(2-(1-(4- ethylphenyl)ethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 494 2.78

(S)-6-chloro-2-hydroxy-N-methoxy-3- (2-(1-methoxy-3-methylbutan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)-N- methylbenzenesulfonamide 4622.79

6-chloro-2-hydroxy-N-methoxy-N- methyl-3-(2-(4-methylcyclohexylamino)-3,4- dioxocyclobut-1-enylamino)benzenesulfonamide 458 2.80

(R)-6-chloro-2-hydroxy-3-(2-(1- hydroxypentan-2-ylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide 4482.81

3-(2-(benzyhydrylamino)-3,4- dioxocyclobut-1-enylamino)-6-chloro-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 528 2.82

(R)-6-chloro-3-(2-(1-cyanobutan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 443/445 2.83

6-chloro-3-(2-(cyclopropylamino)- 3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 402 2.84

6-chloro-3-(2-(2-ethyl-2- phenylhydrazinyl)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy- N-methylbenzenesulfonamide 481 2.85

(S)-6-chloro-3-(3,4-dioxo-2-(1-p- tolylethylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 480 2.86

(S)-6-chloro-3-(2-(1-(4- ethylphenyl)ethylamino)-3,4-dioxocyclobut-1-enylamino)-2- hydroxy-N-methoxy-N-methylbenzenesulfonamide 494 2.87

(S)-6-chloro-3-(2-(1-cyanobutan-2- ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 443/445 2.88

(R)-6-chloro-N-ethyl-2-hydroxy-N- methoxy-3-(2-(1-methoxybutan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)benzenesulfonamide 462 2.89

6-chloro-2-hydroxy-3-(2-((1S,2S)-2- hydroxycyclohexylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide 4602.90

(S)-6-chloro-2-hydroxy-N-methoxy-3- (2-(1-methoxy-3-phenylpropan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)-N- methylbenzenesulfonamide 5102.91

(S)-6-chloro-2-hydroxy-N-methoxy-3- (2-(1-methoxy-4-methylpentan-2-ylamino)-3,4-dioxocyclobut-1- enylamino)-N- methylbenzenesulfonamide 4762.92

6-chloro-3-(3,4-dioxo-2-(1-(pyridin-4- yl)ethylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 467 2.93

6-chloro-3-(2-(1,3-dimethoxypropan- 2-ylamino)-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 464 2.94

6-chloro-3-(3,4-dioxo-2-(2- phenylpropan-2-ylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N- methylbenzenesulfonamide 480 2.95

(R)-6-chloro-2-hydroxy-N-methoxy- N-methyl-3-(2-(1-(1-methyl-1H-pyrazol-4-yl)ethylamino)-3,4- dioxocyclobut-1-enylamino)benzenesulfonamide 470 2.96

6-chloro-2-hydroxy-3-(2-(2- hydroxycyclohexylamino)-3,4-dioxocyclobut-1-enylamino)-N- methoxy-N- methylbenzenesulfonamide 4602.97

(S)-6-chloro-3-(3,4-dioxo-2-(1- (pyrazin-2-yl)propylamino)cyclobut-1-enylamino)-2-hydroxy-N-methoxy- N-methylbenzenesulfonamide 482

Preparation of Intermediate Compounds Intermediate A6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

Step 1: 2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acidmethoxy-methyl-amide N,O-dimethylhydroxylamine (1.98 g, 2 equiv) wassuspended in dry THF (20 ml) and cooled to 0° C. in an ice bath whilestirring vigorously. Triethylamine (4.51 ml, 2 equiv) was addedmaintaining the temperature at 0° C. followed by dropwise addition of2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672page 9) (5 g, 16.22 mmol, 1 equiv) in THF (10 ml) over 30 minutes. Thereaction mixture was stirred at 0° C. for 1 h and then allowed to warmto room temperature overnight. The resulting mixture was filtered andconcentrated in vacuo and the resulting solid was dissolved in EtOAc (75ml), washed with water (3×20 ml), sat. brine (30 ml) dried (MgSO₄) andconcentrated in vacuo to afford the title compound as a solid; [M+H]⁺333.

Step 2: 3-Amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid methoxy-methyl-amide(4.8 g, 14.42 mmol) in dioxane (55 ml) and water (20 ml) was treatedwith concentrated sulphuric acid (20 ml) added dropwise over 30 minutesmaintaining the temperature<30° C. The reaction mixture was heated atreflux for 2.5 h and then allowed to cool to RT. Dioxane was removed invacuo and the resulting aqueous residue was basified with sat. NaHCO₃solution (250 ml) to pH12. The reaction mixture was extracted with EtOAc(3×200 ml) and the combined organic extracts were washed with water(3×100 ml) sat. brine (100 ml), dried (MgSO₄) and concentrated in vacuoto afford the title compound as a brown solid; [M+H]⁺ 266.

Step 3:6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide

A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.83 g, 1.2 equiv)in ethanol (30 ml) was treated with TEA (1.54 g, 1.1 equiv) and thereaction mixture was heated to 45° C.3-Amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (3.7 g,1 equiv) was added portion wise over 30 minutes, with vigorous stirring,maintaining the reaction mixture at 45° C.

The reaction mixture was stirred at 45° C. for 1 hour and then allowedto cool to RT. The solvent was removed in vacuo and the residue waspartitioned between EtOAc (600 ml) and water (2×200 ml). The aqueousportion was separated and extracted with EtOAc (3×200 ml) and thecombined organic extracts were washed with water (3×200 ml) and allowedto stand over night. The resulting solid was collected by filtration anddried in vacuo to afford the title compound. The mother liquor wasevaporated to give a yellow/brown oily solid which was triturated withethanol (100 ml). The solid was collected by filtration, washed withEtOH and dried in vacuo to afford the title compound; [M+H]⁺ 390.

Intermediate B (R)-1-(5-Methyl-furan-2-yl)-propylamine p-toluenesulphonate

This compound was prepared according to the procedure described in US2004/0209946 page 19.

Intermediate C (S)-(Tetrahydro-thiophen-3-yl)amine

This compound was prepared according to the procedure described inSynthesis (1992), (10), 947-9.

Intermediate DA (R)-1-(Tetrahydro-furan-2-yl)-propylamine Step 1:(R)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide

To a cooled (0° C.) solution of (R) tetrahydrofuroic acid (25 g, 215mmol, 1 equiv) in DCM (600 ml) was added TEA (30 ml, 1 equiv), EDCI(61.9 g, 1.5 equiv), N,O-dimethylhydroxylamine (21 g, 1 equiv) followedby DMAP (0.263 g, 0.01 equiv). The reaction mixture was stirred at RTovernight and then washed with 1M HCl and 1M NaOH. The organic portionwas dried (MgSO₄) and concentrated in vacuo to afford the title product;[M+H]⁺ 160, NMR (CDCl₃) 1.9 (1H, m), 2.05 (2H, m), 2.2 (1H, m), 3.2 (3H,s, NCH3), 3.7 (3H, s, OCH3), 3.9 (1H, m, CHO), 4.05 (1H, m, CHO), 4.8(1H, m, CHO).

Step 2: (R)-1-(tetrahydrofuran-2-yl)propan-1-one

To a cooled (0° C.) solution of(R)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide (20.15 g, 1 equiv)in THF (250 ml) was added ethyl magnesium bromide (44.3 ml of a 3Msolution in THF, 1.05 equiv) The reaction was stirred at −78° C. for 1 hand then quenched with saturated NH₄Cl solution. EtOAc was added and theorganic portion was separated and washed further with saturated NH₄Clsolution, dried (MgSO₄) and concentrated in vacuo to afford the titlecompound; NMR (CDCl3) 1.05 (3H, t, CH3), 1.9 (3H, m), 2.2 (1H, m, CH),2.6 (2H, m, CH₂), 3.95 (2H, CH₂O), 4.3 (1H, m, CHO).

Step 3: (R)-1-(tetrahydrofuran-2-yl)propan-1-ol

To a cooled (0° C.) solution of (R)-1-(tetrahydrofuran-2-yl)propan-1-one(16.16 g, 1 equiv) in MeOH was added portionwise sodium tetrahydroborate(4.77 g, 1 equiv). After stirring at 0° C. for 1 hour, the reaction wasquenched with 5M HCl and allowed to stir for further for 10 minutes. Themixture was concentrated in vacuo to remove MeOH and EtOAc and waterwere added. The organic portion was separated and the aqueous layerextracted several times with EtOAc. The combined organic extracts weredried (MgSO₄) and concentrated in vacuo to afford the title compound.

Step 4: (2R)-2-(1-azidopropyl)tetrahydrofuran

To a cooled (0° C.) solution of (R)-1-(tetrahydrofuran-2-yl)propan-1-ol(13.78 g, 1 equiv) in DCM (250 ml) was added TEA (16.07 g, 1.5 equiv)and methanesulfonyl chloride (18.19 g, 1.5 equiv). The reaction wasstirred at 0° C. After 50 min, the reaction was quenched with aq. sat.NaHCO₃. The organic layer was washed with aq. sat NaHCO₃, dried (MgSO₄),filtered and concentrated in vacuo. The reaction was allowed to cool andpartitioned between brine and EtOAc. The aqueous portion was separatedand further extracted with EtOAc. The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude product by chromatography on silica affords the title compound.1.05 (3H, m, CH₃ of two diastereomers), 1.6 (3H, m), 1.95 (3H, m), 3.05(0.5; H, m, CHN₃ of one diastereomer), 3.45 (0.5; H, m, CHN₃ of onediastereomer), 3.8 (1H, m, CHO), 3.9 (2H, m, CH2O).

Step 5: (R)-1-(tetrahydrofuran-2-yl)propan-1-amine

A solution of (2R)-2-(1-azidopropyl)tetrahydrofuran (1.9 g, 12.24 mmol,1 equiv) in EtOH/AcOH (105 ml of a 100:5 mixture) and 10% Pd/C CATCart(12.24 mmol, 1 equiv) was placed under a positive pressure of hydrogenfor 8 hours. The product mixture was concentrated in vacuo and dilutedwith DCM. The mixture was passed down a 10 g SCX-2 cartridge (resinloading 0.67 mmol/g), eluting with methanol followed by 2M ammonia inEtOH. The appropriate fractions were concentrated in vacuo to afford thetitle compound. 1.0 (3H, t, CH3), 1.3 (1H, m), 1.6 (2H, m), 1.9 (3H, m),2.6 (0.5H, m, CHNH2 of one diastereomer), 2.8 (0.5H, m, CHNH2 of onediastereomer), 3.6 (1H, m, CHO), 3.75 (1H, m, CHO), 3.85 (1H, m, CHO).

Intermediate DB (R)-1-(Tetrahydro-furan-2-yl)-propylamine Step 1:(R)-2-((R)-1-Azidopropyl)tetrahydrofuran

This compound was prepared from(S)—(R)-1-(tetrahydro-furan-2-yl)-propan-1-ol analogously to(2R)-2-(1-azidopropyl)tetrahydrofuran (Intermediate DA step 4).

Step 2: tert-Butyl (R)-1-((R)-tetrahydrofuran-2-yl)propylcarbamate

To a solution of (R)-2-((R)-1-azidopropyl)tetrahydrofuran (step 1) (2.11g, 13.6 mmol) in THF (60 ml) and H2O (10 ml) was addedtriphenylphosphine (4.28 g, 16.32 mmol). The reaction was heated at 50°C. overnight and then allowed to cool to RT. Sodium bicarbonate (11.42g, 136 mmol) and Boc-anhydride (4.16 g, 19.04 mmol) were added and thereaction mixture was heated at 40° C. The reaction was allowed to coolto RT and EtOAc was added. The aqueous and organic layers wereseparated. The aqueous layer was extracted with EtOAc. The combinedorganic layers were dried (MgSO4), filtered and concentrated in vacuo.The crude product mixture was purified by flash chromatography on silicagel (40 g) eluting with an EtOAc/iso-hexane (gradient 0-40%) to affordthe title product; ¹H NMR (CDCl₃) δ 0.98 (3H, t, CH3), 1.45 (9H, s,(CH3)3), 1.6 (3H, m), 1.9 (3H, m), 3.5 (1H, m), 3.7 (1H, m), 3.85 (2H,m), 4.6 (1H, m).

Step 3: (R)-1-((R)-tetrahydrofuran-2-yl)propan-1-amine

To a solution of tert-butyl(R)-1-((R)-tetrahydrofuran-2-yl)propylcarbamate (2.67 g, 11.64 mmol) in1,4-dioxane (80 ml) was added 5M HCl (5 ml). The reaction was thenheated at 70° C. for 5.5 hours and after cooling to RT, the mixture wasconcentrated in vacuo to afford the title compound; ¹H NMR (MeOD) δ1.09(3H, t, CH3), 1.7 (3H, m), 2.0 (2H, m), 2.15 (1H, m), 3.0 (1H, m), 3.88(3H, m).

Intermediate DC 1-(6-methylpyridin-2-yl)propan-1-amine

This compound was prepared from 1-(6-methyl-pyridin-2-yl)-propan-1-olanalogously to (R)-1-(tetrahydro-furan-2-yl)-propylamine (IntermediateDB). The final deprotection step was carried out using 5% TFA in DCM;[M+H]⁺ 151.

Intermediate DD 1-(pyridin-3-yl)propan-1-amine

This compound was prepared from 1-pyridin-3-yl-propan-1-ol analogouslyto (R)-1-(tetrahydro-furan-2-yl)-propylamine (Intermediate DB). Thefinal deprotection step was carried out using 5% TFA in DCM; [M+H]⁺ 136.

Intermediate E((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylaminepara-toluenesulfonate salt Step 1:[(R)-1-(5-Methyl-furan-2-yl)-propyl]carbamic acid tert-butyl ester

An ice-cooled solution of (R)-1-(5-methyl-furan-2-yl)-propylamine PTSAsalt (591 mg, 1.90 mmol) (prepared according to the procedure describedin US 2004/0209946 (page 19) and Et₃N (0.264 ml, 1.90 mmol) in dry MeCN(4 ml) was treated with BOC anhydride (456 mg, 2.09 mmol) at roomtemperature under an inert atmosphere of nitrogen. The reaction mixturewas stirred at 0° C. for 30 minutes and allowed to warm to roomtemperature. The solvent was evaporated in vacuo and the resulting oilwas dissolved in EtOAc (20 ml) and washed with 1M HCl (10 ml), Na₂SO₄(10 ml), brine (10 ml), dried (MgSO₄) and concentrated in vacuo. Theresulting oil was dissolved in a minimal volume of EtOH and trituratedwith EtOAc/Et₂O to afford the title compound; [M+H]⁺ 332

Step 2: [(R)-1-(2R,5R)-(5-Methyl-tetrahydro-furan-2-yl)-propyl]-carbamicacid tert-butyl ester

10% Pd/C (55 mg) was added to a solution of[(R)-1-(2R,5R)-(5-methyl-furan-2-yl)-propyl]-carbamic acid tert-butylester (453 mg, 1.89 mmol) in dry MeOH (20 ml) at room temperature underan inert atmosphere of nitrogen. The resulting mixture was placed undera positive atmosphere of hydrogen and stirred vigorously. The catalystwas removed by filtration and the filtrate was reduced in vacuo toafford the title compound as a mixture of two diastereomers.

Step 3: ((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylaminepara-toluenesulfonate salt

To an ice-cooled solution of[(R)-1-(2R,5R)-(5-methyl-tetrahydro-furan-2-yl)-propyl]-carbamic acidtert-butyl ester (416 mg, 1.71 mmol) in dry DCM (4 ml) was added TFA(200 μl, 1.41 mmol) under an inert atmosphere of nitrogen. Afterstirring at room temperature for 3 h, the mixture was diluted with EtOAc(15 ml) and washed with saturated aqueous Na₂CO₃. The organic portionwas dried (Na₂SO₄) and then para-toluenesulfonic acid (147 mg, 0.77mmol) was added. After stirring, the solvent was removed in vacuo andrecrystallisation from MeCN affords the title compound as a white solid.¹H NMR (DMSO) 0.90 (3H, t, CH3), 1.20 (3H, d, CH3), 1.45 (2H, m, 2×CH),1.59 (1H, m, CH), 1.65 (1H, m, CH), 1.95 (2H, m, CH2), 2.30 (3H, s,CH3), 2.93 (1H, m, CH), 3.75 (1H, dd, CH), 3.95 (1H, m, CH), 7.10 (2H,d, 2×CH), 7.48 (2H, d, 2×CH), 7.75 (3H, s, NH3+).

Intermediate FA6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamideStep 1: 2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acidethyl-methoxy-amide

N-Ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) (3.39 g,30.4 mmol) was suspended in dry THF (20 ml) and cooled to 0° C. in anice bath while stirring. TEA (4.24 ml, 30.4 mmol) was added followed bydropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonylchloride (US 2007/0249672 page 9) (4.68 g, 15.19 mmol) in THF (10 ml)over 2.5 hours. The reaction mixture was stirred at room temperature for30 minutes. The reaction mixture was diluted with EtOAc and washed withH₂O, brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by flash chromatography, eluting with 0-10% EtOAc iniso-hexane, to yield a white solid [M+H]⁺ 347.2

Step 2: 3-Amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide

2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid ethyl-methoxy-amide(2.7 g, 7.78 mmol) in dioxane (15 ml) was treated with a mixture ofconcentrated sulphuric acid (3.5 ml) and water (3.5 ml). The reactionmixture was heated at 80° C. for a total of 8 h and then allowed to coolto RT. Dioxane was removed in vacuo and the resulting aqueous mixturewas treated with 1M NaOH (aq) until pH7 was attained. The reactionmixture was extracted with EtOAc, dried (MgSO₄) and concentrated invacuo to afford the title compound as a brown solid; [M+H]⁺ 281.1.

Step 3:6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide

A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (0.30 g, 1.76 mmol)in ethanol (5 ml) was treated with TEA (250 μl, 1.80 mmol) and thereaction mixture was heated to 45° C. A solution of3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (0.58 g,2.07 mmol) in EtOH (5 ml) was added dropwise to the reaction mixture.The reaction mixture was stirred at 45° C. for 1 hour and thenconcentrated in vacuo. The residue was purified using flashchromatography (50% EtOAc in iso-hexane) to furnish a solid [M+H]⁺405.2.

Intermediate FB3-(4-Chloro-2-hydroxy-3-(isoxazolidin-2-ylsulfonyl)phenylamino)-4-ethoxycyclobut-3-ene-1,2-dione

This compound was prepared analogously to6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide(Intermediate FA) by replacing N-ethyl-O-methylhydroxylaminehydrochloride (Intermediate G) with isoxazolidine hydrochloride. [M+H]⁺402.9

Intermediate FC and FD

These compounds namely,3-[4-chloro-2-hydroxy-3-((S)-4-hydroxy-isoxazolidine-2-sulfonyl)-phenylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione(Intermediate FC) and3-[4-chloro-2-hydroxy-3-((R)-4-hydroxy-isoxazolidine-2-sulfonyl)-phenylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione(Intermediate FD) are prepared analogously to6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide(Intermediate FA) by replacing N-ethyl-O-methylhydroxylaminehydrochloride (Intermediate G) with hydrochloride salts of either(S)-isoxazolidin-4-ol (Intermediate I) or (R)-Isoxazolidin-4-ol(Intermediate J). [M+H]⁺ 418.9 and [M+H]⁺ 418.9.

Intermediate FE6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-(2-methoxy-ethoxy)-N-methyl-benzenesulfonamide

This compound was prepared analogously to6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide(Intermediate FA) by replacing N-ethyl-O-methylhydroxylaminehydrochloride (Intermediate G) withO-(2-Methoxy-ethyl)-N-methyl-hydroxylamine (Intermediate K). [M+H]⁺ 435

Intermediate G N-Ethyl-O-methyl-hydroxylamine Hydrochloride Step 1:N-methoxy Carbamic Acid Ethyl Ester

A stirred mixture of ethyl chloroformate (10.78 g, 99 mmol) andO-methylhydroxylamine hydrochloride (12.4 g, 148 mmol) in DCM (400 ml)was cooled using an acetonitrile-cardice bath. TEA (25.05 g, 248 mmol)was added dropwise over 10 minutes, and cooling was maintained for afurther 10 minutes. The reaction mixture was stirred at room temperaturefor 30 minutes, washed with 1M HCl (aq), dried (MgSO₄) and concentratedin vacuo, to give a mixture of oil and solid. The oil was isolated, andNMR was consistent with proposed product; ¹H NMR (CDCl3) 1.3 (3H, t,CH3), 3.7 (3H, s, CH3), 4.2 (2H, q, CH2), 7.3 (1H, s)

Step 2: N-Ethyl-O-methyl-hydroxylamine Hydrochloride

A stirred mixture of N-methoxy carbamic acid ethyl ester (10.45 g, 88mmol) in DMF (50 ml) was cooled using an ice-bath. Sodium hydride (60%dispersion in oil) (3.65 g, 91 mmol) was added portionwise and thereaction mixture was stirred at room temperature for 1 hour.

Bromoethane (9.56 g, 88 mmol) was added portionwise, and reactionmixture was heated at 80° C. for 4 hours. The mixture was partitionedbetween H₂O and 1:1 EtOAc/Et₂O. The organic layer was washed withfurther H₂O, dried (MgSO₄) and concentrated in vacuo, to give an oil.The oil was heated at 65° C. for 5 hours in a mixture of KOH (12.4 g,221 mmol), H₂O (15 ml) and EtOH (15 ml). The resulting solution wasdistilled into 2M HCl (aq), and concentrated in vacuo, to furnish anoil. ¹H NMR (CDCl3) 1.2 (3H, t, CH3), 3.2 (2H, q, CH2), 3.9 (3H, s,CH3), 12.1 (2H, s)

Intermediate H (R)-2-Amino-3-methyl-butan-1-ol

This compound was prepared according to the procedure described in WO957257, Example 7.

Intermediate I and J (S)-Isoxazolidin-4-ol and (R)-Isoxazolidin-4-ol

These compounds namely (S)-isoxazolidin-4-ol (Intermediate I) and(R)-Isoxazolidin-4-ol (Intermediate J) are prepared according to theprocedure of Journal of Molecular Catalysis B: Enzymatic (2001),11(4-6), 255-263.

Intermediate K O-(2-Methoxy-ethyl)-N-methyl-hydroxylamine

This compound is prepared according to the procedure described in‘Preparation of 7-aminopyrazolo[1,5-a]pyrimidines as agriculturalfungicides and pesticides. Ger. Offen. (2003), 50 pp. DE 10223917 page42.

Intermediate L3-(2-Ethoxy-3,4-dioxocyclobut-1-enylamino)-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide Step 1:3-Amino-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide

A dispersion of 10% Pd/C (200 mg) in a solution of3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Int. FAstep 2) (400 mg, 1.425 mmol) in EtOH (50 ml) was placed under a positivepressure of hydrogen at 0.5 bar above atmospheric pressure. After 5hours, the catalyst was removed by filtration through Celite® (filtermaterial), and the filtrate was reduced in vacuo. The resulting solidwas used in the next step, without further purification.

Step 2:3-(2-Ethoxy-3,4-dioxocyclobut-1-enylamino)-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide

This compound was prepared analogously to6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide(Intermediate A step 3) by replacing3-amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide with3-amino-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide (step 1). [M+H]⁺371

Intermediate M 1-(Pyrazin-2-yl)propan-1-amine Step 1:2-(1-Azidopropyl)pyrazine

The title compound is prepared from 1-(pyrazin-2-yl)propan-1-ol(prepared according to the procedure of ‘Some reactions of monosubstituted pyrazine monoxides’ Journal of Heterocyclic Chemistry(1982), 19(5), 1061-7, Compound 18) analogously to(2R)-2-(1-azidopropyl)tetrahydrofuran (Intermediate DA, step 4).

Step 2: 1-(Pyrazin-2-yl)propan-1-amine

The 2-(1-azidopropyl)pyrazine (56 mg) was dissolved in the THF (5 ml)and water (1 ml) and the PS—PPh₃ (225 mg) added. The reaction mixturewas heated to 50° C. and left to stir for approx. 20 hours. The mixturewas filtered under vacuum and rinsed with DCM (a precipitate formed andre-dissolved with MeOH) then MeOH. The filtrate was evaporated to yieldthe title compound as a yellow oil which was used without furtherpurification. [M+H]⁺ 138.

Intermediate N (S)-1-methoxy-4-methylpentan-2-amine

(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to astirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF(10 ml) under nitrogen. The resulting mixture was allowed to warm toroom temperature and stirred for ˜10 minutes and then treated with MeI(0.121 ml, 1.939 mmol). After stirring for 30 minutes the reactionmixture was quenched by addition of saturated NH₄Cl (aq) (˜20 ml) andextracted with EtOAc (25 ml×2). The combined organic phases were driedover MgSO₄, filtered under vacuum and the filtrate was evaporated toafford an orange oil. The oil was purified by chromatography on silicaeluting with 10% (2M NH₃ in MeOH)/DCM to afford the title compound whichwas used without further purification.

Intermediate O (R)-1-(pyridin-2-yl)propan-1-amine Step 1:(S,E)-3-Methyl-N-(pyridin-2-ylmethylene)-1-(trimethylsilyloxy)butan-2-amine

To a solution of pyridyl-2-carboxaldehyde (14.22 g, 133 mmol) and(R)-Valinol (13.7 g, 133 mmol) in DCM (150 ml) was added MgSO₄ (63.9 g,531 mmol). The reaction was allowed to stir at room temperatureovernight and then filtered to remove MgSO₄ and concentrated in vacuo.The residue was dissolved in DCM (150 ml) and cooled on an ice bath. TEA(14.78 g, 146 mmol) and TMSCI (15.87 g, 146 mmol) were added and themixture was stirred at room temperature overnight. The mixture wasfiltered and the filtrate was concentrated in vacuo The resultingresidue was taken up in 1:1 Et2O:cyclohexane. The solid was filtered offand the filtrates concentrated to afford the title compound as anorange/brown oil.

Step 2: (S)-3-methyl-2-((R)-1-(pyridin-2-yl)propylamino)butan-1-ol

To a solution of imine (10.78 g, 40.8 mmol) in THF (100 ml) cooled to−78° C. was added a solution of ethyl lithium (26.4 ml, 1.7 M in dibutylether). The mixture was stirred at −78° C. and after 1 h, 5M HCl wasadded and stirring continued at RT overnight. The reaction mixture wasdiluted with EtOAc and H₂O. The aqueous and organic layers wereseparated and the aqueous layer was further extracted with EtOAc. Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo to afford the title compound which was used without furtherpurification. [M+H]⁺ 223.1.

Step 3: (R)-1-(pyridin-2-yl)propan-1-amine

To a solution of(S)-3-methyl-2-((R)-1-(pyridin-2-yl)propylamino)butan-1-ol (step 2,crude product) (40.8 mmol) in MeOH (250 ml) was added methylamine (60 mlof a 40% aqueous solution) followed by a solution of periodic acid (37.2g, 163 mmol) in water (70 ml). The mixture was stirred at RT overnightand the resulting white solid precipitate was filtered off. The filtratewas concentrated in vacuo to remove the MeOH. The residual aqueous layerwas then extracted with EtOAc. The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo Purification of the crudeproduct by chromatography on silica eluting with a 0-20% MeOH/DCMgradient affords the title product; [M+H}+137.

1. A compound of formula I

or solvates, hydrates or pharmaceutically acceptable salts thereof, wherein R¹ is H, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, (C₁-C₄ alkyl)-3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, (C₁-C₄ alkyl)-3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, C₁-C₆ alkyl optionally substituted by one or more halogen atoms, CN or OH groups, C₁-C₆ alkoxy optionally substituted by one or more halogen atoms or OH groups, or an ether group containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group is optionally substituted by one or more substituents each independently selected from OH, halogen, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups and a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups; R² is a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, (C₁-C₄ alkyl)-3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, (C₁-C₄ alkyl)-3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, C₁-C₆ alkyl optionally substituted by one or more halogen atoms, CN or OH groups, C₁-C₆ alkoxy optionally substituted by one or more halogen atoms or OH groups, or an ether group containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, wherein the ether group is optionally substituted by one or more substituents each independently selected from OH, halogen, a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups and a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups; or R¹ and R² together with the carbon atom to which they are attached form 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, or a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups; R³ is hydrogen, halogen or cyano; R⁴ is H, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl or (C₁-C₄ alkyl)-R⁶, wherein the alkyl groups are each optionally substituted by one or more halogen atoms; R⁵ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, (C₁-C₄ alkyl)-C₃-C₈ cycloalkyl or (C₁-C₄ alkyl)-C₅-C₈ cycloalkenyl, wherein the alkyl groups are each optionally substituted by one or more halogen atoms; or R⁴ and R⁵, together with the nitrogen and oxygen atoms to which they are attached, form a 5 to 10 membered heterocyclic group optionally substituted by one or more Z groups; R⁶ is selected from a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, NR⁷R⁹, NR⁷(SO₂)R⁹, (SO₂)NR⁷R⁸, (SO₂)R⁹, NR⁷C(O)R⁹, C(O)NR⁷R⁹, NR⁷C(O)NR⁸R⁹, NR⁷C(O)OR⁹, C(O)OR⁷, OC(O)R⁹, OC(O)NR⁷, C(O)R⁹, SR⁷, CN and NO₂; R⁷ and R⁸ are each independently selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl and —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl; R⁹ is selected from H, C₁-C₆ alkyl, —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the alkyl groups and ring systems is optionally substituted by OH, halo, C₁-C₃ alkyl and C₁-C₃ alkoxy; X is CR¹⁴ or N; Z is independently selected from OH; a 3 to 10 membered carbocyclic group; a 3 to 10 membered heterocyclic group; benzyl; C₁-C₆ alkyl optionally substituted by one or more halogen atoms, CN or OH groups; C₁-C₆ alkoxy optionally substituted by one or more halogen atoms, CN or OH groups; -Oaryl; -Obenzyl; —O(CH₂)_(a)C(O)E; NR¹⁰(SO₂)R¹²; (SO₂)NR¹⁰R¹¹; (SO₂)R¹²; NR¹⁰C(O)R¹²; C(O)NR¹⁰R¹²; NR¹⁰C(O)NR¹¹R¹²; NR¹⁰C(O)OR¹²; NR¹⁰R¹²; C(O)OR¹⁰; OC(O)R¹²; OC(O)NR¹⁰; C(O)R¹²; SR¹²; CN; NO₂; and halogen; or where there are two or more Z substitutents, two Z substituents together with the atoms to which they are attached optionally form a 5- to 7-membered carbocyclic or a 4- to 7-membered heterocyclic substituent fused to the ring system; a is 0, 1, 2, 3 or 4, wherein the alkylene group is optionally substituted by OH or NH₂ when a is 1, 2, 3 or 4; E is NR¹⁰R¹² or OR¹²; each R¹⁰ and R¹¹ are independently selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₀ cycloalkenyl and —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl; each R¹² is selected from H, C₁-C₆ alkyl, —(C₁-C₃ alkylene)-C₃-C₁₀ cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the ring systems is optionally substituted by OH, halo, C₁-C₃ alkyl and C₁-C₃ alkoxy; and R¹⁴ is H or C₁-C₆ alkyl.
 2. A compound according to claim 1, wherein R¹ is H or C₁-C₄ alkyl.
 3. A compound according to claim 1, wherein R¹ is H or C₁-C₄ alkyl; R² is C₁-C₆ alkyl optionally substituted by one or more halogen atoms, CN or OH groups, an ether group containing 2 to 10 carbon atoms and 1 to 3 oxygen atoms, a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups, or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; or R¹ and R², together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups.
 4. A compound according to claim 1, wherein R³ is halogen.
 5. A compound according to claim 1, wherein R⁴ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl or (C₁-C₃ alkyl)-C₃-C₆ cycloalkyl.
 6. A compound according to claim 1, wherein R⁵ is C₁-C₆ alkyl.
 7. A compound according to claim 1, wherein X is CH.
 8. A compound according to claim 1 which is selected from: Structure


9. A compound according to claim 1 for use as a pharmaceutical.
 10. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of inflammatory or allergic conditions or diseases.
 11. Use according to claim 10, wherein the condition is COPD.
 12. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or excipient.
 13. A method for the prevention or treatment of a CXCR2 receptor mediated condition or disease comprising administering an effective amount of at least one compound according to claim 1 to a subject in need of such treatment.
 14. A process for the preparation of a compound according to claim 1, the process comprising reacting a compound of formula II

wherein R³, R⁴ and R⁵ are as defined in claim 1, with a compound of formula III

Wherein X, R¹ and R² are as defined in claim 1; and isolating the product. 